XRCC2
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Homologous recombination (HR) factors are crucial for DSB repair and processing stalled replication forks. RAD51 paralogs, including RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, have emerged as essential tumour suppressors, forming two subcomplexes, BCDX2 and CX3. Mutations in these genes are associated with cancer susceptibility and Fanconi anaemia, yet their biochemical activities remain unclear. This study reveals a linear arrangement of BCDX2 subunits compared to the RAD51 ring. BCDX2 shows a strong affinity towards single-stranded DNA (ssDNA) via unique binding mechanism compared to RAD51, and a contribution of DX2 subunits in binding branched DNA substrates. We demonstrate that BCDX2 facilitates RAD51 loading on ssDNA by suppressing the cooperative requirement of RAD51 binding to DNA and stabilizing the filament. Notably, BCDX2 also promotes RAD51 loading on short ssDNA and reversed replication fork substrates. Moreover, while mutants defective in ssDNA binding retain the ability to bind branched DNA substrates, they still facilitate RAD51 loading onto reversed replication forks. Our study provides mechanistic insights into how the BCDX2 complex stimulates the formation of BRCA2-independent RAD51 filaments on short stretches of ssDNA present at ssDNA gaps or stalled replication forks, highlighting its role in genome maintenance and DNA repair.
- MeSH
- DNA vazebné proteiny * metabolismus genetika MeSH
- jednovláknová DNA * metabolismus genetika MeSH
- lidé MeSH
- multiproteinové komplexy MeSH
- mutace MeSH
- rekombinasa Rad51 * metabolismus genetika MeSH
- replikace DNA * genetika MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: We aimed to detect single nucleotide polymorphisms (SNPs) and mutations in DNA repair genes and their possible association with myelodysplastic syndrome (MDS). METHODS: Targeted enrichment resequencing of 84 DNA repair genes was initially performed on a screening cohort of MDS patients. Real-time polymerase chain reaction was used for genotyping selected SNPs in the validation cohort of patients. RESULTS: A heterozygous frameshift mutation in the XRCC2 gene was identified. It leads to the formation of a truncated non-functional protein and decreased XRCC2 expression level. Decreased expression levels of all DNA repair genes functionally connected with mutated XRCC2 were also present. Moreover, a synonymous substitution in the PRKDC gene and 2 missense mutations in the SMUG1 and XRCC1 genes were also found. In the screening cohort, 6 candidate SNPs were associated with the tendency to develop MDS: rs4135113 (TDG, p = 0.03), rs12917 (MGMT, p = 0.003), rs2230641 (CCNH, p = 0.01), rs2228529 and rs2228526 (ERCC6, p = 0.04 and p = 0.03), and rs1799977 (MLH1, p = 0.04). In the validation cohort, only a polymorphism in MLH1 was significantly associated with development of MDS in patients with poor cytogenetics (p = 0.0004). CONCLUSION: Our study demonstrates that genetic variants are present in DNA repair genes of MDS patients and may be associated with susceptibility to MDS.
- MeSH
- DNA vazebné proteiny genetika MeSH
- genetická predispozice k nemoci MeSH
- jaderné proteiny genetika MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- MutL homolog 1 genetika MeSH
- myelodysplastické syndromy enzymologie genetika metabolismus MeSH
- oprava DNA * MeSH
- protein XRCC1 genetika MeSH
- proteinkinasa aktivovaná DNA genetika MeSH
- uracil-DNA-glykosidasa genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The high incidence of mutations and cytogenetic abnormalities in patients with myelodysplastic syndrome (MDS) suggests that defects in DNA repair mechanisms. We monitored DNA repair pathways in MDS and their alterations during disease progression. METHODS: Expression profiling of DNA repair genes was performed on CD34+ cells, and paired samples were used for monitoring of RAD51 and XRCC2 gene expression during disease progression. Immunohistochemical staining for RAD51 was done on histology samples. RESULTS: RAD51 and XRCC2 showed differential expression between low-risk and high-risk MDS (P<.0001), whereas RPA3 was generally decreased among the entire cohort (FC=-2.65, P<.0001). We demonstrated that RAD51 and XRCC2 expression gradually decreased during the progression of MDS. Down-regulation of XRCC2 and RAD51 expression was connected with abnormalities on chromosome 7 (P=.0858, P=.0457). Immunohistochemical staining revealed the presence of RAD51 only in the cytoplasm in low-risk MDS, while in both the cytoplasm and nucleus in high-risk MDS. The multivariate analysis identified RAD51 expression level (HR 0.49; P=.01) as significant prognostic factor for overall survival of patients with MDS. CONCLUSIONS: Our study demonstrates that the expression of DNA repair factors, primarily RAD51 and XRCC2, is deregulated in patients with MDS and presents a specific pattern with respect to prognostic categories.
- MeSH
- biologické markery MeSH
- chromozomální aberace MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- dospělí MeSH
- kostní dřeň patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- myelodysplastické syndromy genetika metabolismus mortalita patologie MeSH
- oprava DNA MeSH
- prognóza MeSH
- regulace genové exprese * MeSH
- rekombinační oprava DNA genetika MeSH
- rekombinasa Rad51 genetika metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The presence of breast cancer in any first-degree female relative in general nearly doubles the risk for a proband and the risk gradually increases with the number of affected relatives. Current advances in molecular oncology and oncogenetics may enable the identification of high-risk individuals with breast-cancer predisposition. The best-known forms of hereditary breast cancer (HBC) are caused by mutations in the high-penetrance genes BRCA1 and BRCA2. Other genes, including PTEN, TP53, STK11/LKB1, CDH1, PALB2, CHEK2, ATM, MRE11, RAD50, NBS1, BRIP1, FANCA, FANCC, FANCM, RAD51, RAD51B, RAD51C, RAD51D, and XRCC2 have been described as high- or moderate-penetrance breast cancer-susceptibility genes. The majority of breast cancer-susceptibility genes code for tumor suppressor proteins that are involved in critical processes of DNA repair pathways. This is of particular importance for those women who, due to their increased risk of breast cancer, may be subjected to more frequent screening but due to their repair deficiency might be at the risk of developing radiation-induced malignancies. It has been proven that cancers arising from the most frequent BRCA1 gene mutation carriers differ significantly from the sporadic disease of age-matched controls in their histopathological appearances and molecular characteristics. The increased depth of mutation detection brought by next-generation sequencing and a better understanding of the mechanisms through which these mutations cause the disease will bring novel insights in terms of oncological prevention, diagnostics, and therapeutic options for HBC patients.
- MeSH
- ATM protein genetika MeSH
- biologické markery MeSH
- checkpoint kinasa 2 genetika MeSH
- fosfohydroláza PTEN genetika MeSH
- genetická predispozice k nemoci * MeSH
- geny BRCA1 MeSH
- geny BRCA2 MeSH
- jaderné proteiny genetika MeSH
- kadheriny genetika MeSH
- lidé MeSH
- mutace MeSH
- nádorové supresorové proteiny genetika MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory prsu genetika patologie MeSH
- penetrance MeSH
- protein-serin-threoninkinasy genetika MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Cervical cancer affects women worldwide, especially in developing countries. Approximately 500,000 cases of this disease are diagnosed per year. The method of choice in the treatment of advanced cervical cancers (in accordance with the International Federation of Gynecology and Obstetrics staging system (FIGO) starting from stage IIB) is combined radiotherapy with concomitant chemotherapy. This treatment provides good tumour control, but it carries a risk of late complications in the irradiated area in 10-15 % of cases. Methylation is one of the methods of epigenetic control, which has an important role in gene expression. Aberrant methylation of normal CpG islands in promoters of tumour suppressor genes such as RB, p53 or DNA reparation genes ATM, BRCA1,2, and RAD51 gene family causes silencing of their function and cell cycle deregulation, which is one of the efficient ways of neoplastic transformation. The significantly decreased expression of molecules involved in DNA response may cause facilitated radiosensitivity in predisposed individuals. We looked for the relationship between hypermethylation of 18 DNA reparation genes and late toxicity occurrence in cervical cancer patients treated by chemoradiotherapy using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The cut-off value for the hypermethylation was set at 10 %. We confirmed significant association between promoter hypermethylation in the XRCC2 gene and occurrence of late grade III-IV toxicity in cervical cancer patients (P = 0.0357). This finding could be useful in the late toxicity prediction in radiotherapy-treated patients.
